This invention relates to certain substituted 3-cyanoquinoline compounds as well as the pharmaceutically acceptable salts thereof. The compounds of the present invention inhibit the action of certain growth factor receptor protein tyrosine kinases (PTK) and other protein kinases thereby inhibiting the abnormal growth of certain cell types. The compounds of this invention are therefore useful for the treatment of certain diseases that are the result of deregulation of these PTKs. The compounds of this invention are anti-cancer agents and are useful for the treatment of cancer in mammals. In addition, the compounds of this invention are useful for the treatment of polycystic kidney disease in mammals. This invention also relates to the manufacture of said 3-cyanoquinolines, their use for the treatment of cancer and polycystic kidney disease, and the pharmaceutical preparations containing them.
Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue located on a protein substrate. Protein tyrosine kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins function as tyrosine kinases and it is by this process that they effect signaling. The interaction of growth factors with these receptors is a necessary event in normal regulation of cell growth. However, under certain conditions, as a result of either mutation or overexpression, these receptors can become deregulated. The result of this is uncontrolled cell proliferation which can lead to tumor growth and ultimately to the disease known as cancer [Wilks A. F., Adv. Cancer Res., 60, 43 (1993) and Parsons, J. T.; Parsons, S. J., Important Advances in Oncology, DeVita V. T. Ed., J. B. Lippincott Co., Phila., 3 (1993)]. Among the growth factor receptor kinases and their proto-oncogenes that have been identified and which are targets of the compounds of this invention are the epidermal growth factor receptor kinase (EGF-R kinase, the protein product of the erbB oncogene), and the product produced by the Her2 (also referred to as the neu or erbB-2) oncogene. Since the phosphorylation event is a necessary signal for cell division to occur and since overexpressed or mutated kinases have been associated with cancer, an inhibitor of this event, a protein tyrosine kinase inhibitor, will have therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. For example, overexpression of the receptor kinase product of the Her2 oncogene has been associated with human breast and ovarian cancers [Slamon, D. J., et. al., Science, 244, 707 (1989) and Science, 235, 1146 (1987)]. Deregulation of EGF-R kinase has been associated with epidermoid tumors [Reiss, M., et. al., Cancer Res., 51, 6254 (1991)], breast tumors [Macias, A., et. al., Anticancer Res., 7, 459 (1987)], and tumors involving other major organs [Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)]. Because of the importance of the role played by deregulated receptor kinases in the pathogenesis of cancer, many recent studies have dealt with the development of specific PTK inhibitors as potential anti-cancer therapeutic agents [some recent reviews: Burke, T. R., Drugs Future, 17, 119 (1992) and Chang, C. J.; Geahlen, R. L., J. Nat. Prod., 55, 1529 (1992)]. The compounds of this invention inhibit the kinase activity of EGF-R and Her2 and are therefore useful for treating certain disease states, such as cancer, that result, at least in part, from deregulation of these receptors. The compounds of this invention are also useful for the treatment and prevention of certain pre-cancerous conditions, such as the growth of colon polyps, that result, at least in part, from deregulation of these receptors.
It is also known that deregulation of EGF receptors is a factor in the growth of epithelial cysts in the disease described as polycystic kidney disease [Du J., Wilson P. D., Amer. J. Physiol., 269(2 Pt 1), 487 (1995); Nauta, J., et al., Pediatric Research, 37(6), 755 (1995); Gattone, V. H., et al., Developmental. Biology, 169(2), 504 (1995); Wilson, P. D., et al., Eur. J. Cell Biol., 61(1), 131,(1993)]. The compounds of this invention, which inhibit the catalytic function of the EGF receptors, are consequently useful for the treatment of this disease.
Some 3-cyanoquinoline derivatives are inhibitors of tyrosine kinases and are described in the application WO9843960 (U.S. Pat. No. 6,002,008). These 3-cyanoquinolines may be substituted at carbon-5 through carbon-8 with an unsubstituted phenyl, alkene or alkyne group. Applications WO0018761 and WO0018740 also describe 3-cyanoquinoline inhibitors. A 3-cyanoquinoline with a 4-(2-methylanilino) substituent having gastric (H+/K+)-ATPase inhibitory activity at high concentrations has been described [Ife, R., J. Med. Chem., 35(18), 3413 (1992)].
The compounds of the present invention are 3-cyanoquinolines which inhibit the activity of protein kinases that are required for cell growth and differentiation and are therefore useful for the treatment of certain diseases that result from activity of these protein kinases. In particular, the compounds of this invention inhibit the kinase activity of EGF-R and Her2 kinases. The compounds of this invention are anti-cancer agents and are useful for the treatment of cancer in mammals. Further, the compounds of this invention are useful for the treatment of polycystic kidney disease in mammals.
In accordance with the present invention, there is provided compounds represented by Formula (I): 
wherein:
Z is xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NRxe2x80x94;
R is alkyl of 1 to 6 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or
X is pyridinyl, pyrimidinyl, or aryl and may optionally be mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)Sxe2x80x94, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino; or
X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms independently selected from N, O, and S; wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono-, di-, tri-, or tetra-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)Sxe2x80x94, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5Sxe2x80x94), benzoyl, benzyl, amino, alkylamino of 1 to 6,carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino; or
X is the radical 
E is pyridinyl, pyrimidinyl, or aryl optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)Sxe2x80x94, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
T is substituted on E at carbon and is xe2x80x94NH(CH2)mxe2x80x94, xe2x80x94O(CH2)mxe2x80x94, xe2x80x94S(CH2)mxe2x80x94, xe2x80x94NR(CH2)mxe2x80x94, xe2x80x94(CH2)mxe2x80x94 xe2x80x94(CH2)mNHxe2x80x94, xe2x80x94(CH2)mOxe2x80x94, xe2x80x94(CH2)mSxe2x80x94, or xe2x80x94(CH2)mNRxe2x80x94;
L is an aryl ring optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)Sxe2x80x94, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino; or
L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms independently selected from N, O, and S; wherein the heteroaryl ring may be optionally mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)Sxe2x80x94, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5Sxe2x80x94), benzoyl, benzyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
Pyridinyl, pyrimidinyl, or aryl are pyridinyl, pyrimidinyl, or aryl radicals, respectively, optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)Sxe2x80x94, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino;
G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkenyloxy of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2 to 6 carbon atoms, alkenoyloxy of 3 to 8 carbon atoms, alkynoyloxy of 3 to 8 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkenoyloxymethyl of 4 to 9 carbon atoms, alkynoyloxymethyl of 4 to 9 carbon atoms, alkoxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)Sxe2x80x94, alkylsulphinyl of 1 to 6 carbon atoms, alkylsulphonyl of 1 to 6 carbon atoms, alkylsulfonamido of 1 to 6 carbon atoms, alkenylsulfonamido of 2 to 6 carbon atoms, alkynylsulfonamido of 2 to 6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5Sxe2x80x94), benzyl, amino, hydroxyamino, alkoxyamino of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6 to 12 carbon atoms, phenylamino, benzylamino, R2NH, 
R8R9xe2x80x94CHxe2x80x94Mxe2x80x94(C(R6)2)kxe2x80x94Yxe2x80x94,
R7xe2x80x94(C(R6)2)gxe2x80x94Yxe2x80x94, R7xe2x80x94(C(R6)2)pxe2x80x94Mxe2x80x94(C(R6)2)kxe2x80x94Yxe2x80x94, or Het-(C(R6)2)qxe2x80x94Wxe2x80x94(C(R6)2)kxe2x80x94Yxe2x80x94, provided that either G2 or G3 or both G2 and G3 are R2NH;
Y is a divalent radical selected from the group consisting of 
R7 is xe2x80x94NR6R6, xe2x80x94OR6, xe2x80x94J, xe2x80x94N(R6)3 +Qxe2x88x92, or xe2x80x94NR6(OR6);
M is  greater than NR6, xe2x80x94Oxe2x80x94,  greater than Nxe2x80x94(C(R6)2)pNR6R6, or  greater than Nxe2x80x94(C(R6)2)pxe2x80x94OR6;
W is  greater than NR6, xe2x80x94Oxe2x80x94 or is a bond;
Het is a heterocyclic radical selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and 
which may be optionally mono- or di-substituted on carbon with R6, hydroxy, xe2x80x94N(R6)2, xe2x80x94OR6, xe2x80x94(C(R6)2)sOR6 or xe2x80x94(C(R6)2)sN(R6)2;
optionally mono-substituted on nitrogen with R6; and
optionally mono or di-substituted on a saturated carbon with divalent radicals xe2x80x94Oxe2x80x94 or xe2x80x94O(C(R6)2)sOxe2x80x94;
R6 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, carboxyalkyl 2 to 7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC1-C6)Sxe2x80x94, hydroxy, carboxyl, carboalkoxy of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C6H5Sxe2x80x94), benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms; provided that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
R2, is selected from the group consisting of 
R3 is hydrogen, alkyl of 1 to 6 carbon atoms, carboxy, carboalkoxy of 1 to 6 carbon atoms, phenyl, carboalkyl of 2 to 7 carbon atoms, 
R7xe2x80x94(C(R6)2)sxe2x80x94, R7xe2x80x94(C(R6)2)pxe2x80x94Mxe2x80x94(C(R6)2)rxe2x80x94, R8R9xe2x80x94CHxe2x80x94Mxe2x80x94(C(R6)2)rxe2x80x94, or Het-(C(R6)2)qxe2x80x94Wxe2x80x94(C(R6)2)rxe2x80x94;
R4 is xe2x80x94NR6R6, xe2x80x94OR6, xe2x80x94SR6, R7xe2x80x94(C(R6)2)pxe2x80x94Sxe2x80x94, R7xe2x80x94(C(R6)2)pxe2x80x94N(R6)xe2x80x94, R7xe2x80x94(C(R6)2)pxe2x80x94Oxe2x80x94, R8R9xe2x80x94CHxe2x80x94N(R6)xe2x80x94, R8R9xe2x80x94CHxe2x80x94Sxe2x80x94, R8R9xe2x80x94CHxe2x80x94Oxe2x80x94, Het-(C(R6)2)qxe2x80x94N(R6)xe2x80x94, Het-(C(R6)2)qxe2x80x94Sxe2x80x94, Het-(C(R6)2)qxe2x80x94Oxe2x80x94, 
cysteine, or a peptide comprised of 2 to 10 native amino acid residues containing at least one unoxidized cysteine residue wherein R4 is bound to the rest of the molecule through the sulfur atom of one or more of the cysteine residues;
R8 and R9 are each, independently, xe2x80x94(C(R6)2)rNR6R6, or xe2x80x94(C(R6)2)rOR6;
J is independently hydrogen, chlorine, fluorine, or bromine;
a is an integer of 0-1;
g is an integer of 1-6;
k is an integer of 0-4;
n is an integer of 0-1;
m is an integer of 0-3;
p is an integer of 2-4;
q is an integer of 0-4;
r is an integer of 1-4;
s is an integer of 1-6
u is an integer of 2-6;
Qxe2x88x92 is a counterion selected from salts formed from organic and inorganic acids;
provided that:
a. when R6 is alkenyl of 2 to 7 carbon atoms or alkynyl of 2 to 7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
b. when Y is xe2x80x94NR6xe2x80x94 and R7 is xe2x80x94NR6R6, xe2x80x94N(R6)3 +Qxe2x88x92, or xe2x80x94NR6(OR6), then g is an integer of 2 to 6;
c. when M is xe2x80x94Oxe2x80x94 and R7 is xe2x80x94OR6 then p is an integer of 1 to 4;
d. when Y is xe2x80x94NR6xe2x80x94 then k is an integer of 2 to 4;
e. when Y is xe2x80x94Oxe2x80x94 and M or W is xe2x80x94Oxe2x80x94 then k is an integer of 1 to 4;
f. when W is not a bond with Het bonded through a nitrogen atom then q is an integer of 2 to 4 and when W is a bond with Het bonded through a nitrogen atom and Y is xe2x80x94Oxe2x80x94 or xe2x80x94NR6xe2x80x94 then k is an integer of 2 to 4;
or a pharmaceutically acceptable salt thereof.